Pathology-White Cell Disorder Pathology Flashcards
What is the marker for the hematopoietic stem cell in the bone marrow?
CD34
How does differentiation of the hematopoietic stem cell proceed down the lymphoid route?
The lymphoid stem cell (blast) can differentiate into a B lymphoblast or a T lymphoblast. They can then become naive B cells and T cells respectively. The naive B cell then becomes a plasma cell. The naive T cells differentiate into CD8+ or CD4+ T cells.
How does differentiation of the hematopoietic stem cell proceed down the myeloid route?
The myeloid stem cell (blast) can differentiate into an erythroblast and become an RBC, a myeloblast and become a neutrophil, basophil or eosinophil, a monoblast and become a monocyte and a megakaryoblast to become a megakaryocyte.
Normal WBC count
5-10K. < 5K = leukopenia. >10K = leukocytosis.
Common causes of neutropenia
Drug toxicity (chemotherapy blocks hematopoiesis) and severe infection (most of the neutrophils have left the blood and are in the tissue)
How do you treat a patient who is on chemotherapy that has neutropenia?
GM-CSF or G-CSF. Both of these will help to boost the neutrophil count.
Common causes of lymphopenia
Immunodeficiency (DiGeorge failure to develop 3rd and 4th pharyngeal pouch = failure to develop thymus = failure to develop T cells), high cortisol state (induces lymphocytic apoptosis), autoimmune destruction (Lupus produces antibodies against WBCs) and whole body radiation (lymphocytes are most sensitive cells in the body to radiation).
Common causes of neutrophilic leukocytosis
Bacterial infection and tissue necrosis from acute inflammatory process. High cortisol state (marginated pool of neutrophils are released from cortisol breaking the adhesion molecule to the pulmonary endothelium).
Why don’t band cells work as well as grown up neutrophils during acute inflammation?
When they are released early from the bone marrow they have decreased CD16 (Fc receptor). This results in decreased recognition of immunoglobulins that have opsonized invading pathogens.
Common causes of monocytosis
Chronic inflammatory states and malignancy
Common causes of eosinophilia
Allergic reactions, parasitic infections and Hodgkin lymphoma (due to increased IL-5 production)
Common cause of basophilia
CML
Common causes of lymphocytic leukocytosis
Viral infections (CD8+ T-cells are main fighters of virus and are released into the blood in an infection) and Bordetella pertussis (bacteria produces lymphocytosis promoting factor, this prevents lymphocytes from exiting the blood and going to the lymph nodes)
A 17 year old boy comes to see you complaining of a sore throat, fever and fatigue. Physical exam reveals posterior cervical lymphadenopathy and splenomegaly. Peripheral blood smear is shown below. What is causing his condition?
Note the atypical lymphocyte (CD8+ T-cell nucleus much larger than RBCs with abundant cytoplasm, note that it looks like a monocyte). This patient has infectious mononucleosis. Salivary transmission of EBV is the most common cause and CMV is the less common cause. EBV targets the oropharynx, liver and B cells during an infection.
A 17 year old boy comes to see you complaining of a sore throat, fever and fatigue. Physical exam reveals posterior cervical lymphadenopathy and splenomegaly. Labs reveal a high white count and atypical lymphocytes. Which area of the lymph node is causing lymphadenopathy?
He has infectious mononucleosis, most likely from an EBV infection. The immune response to this is release of CD8+ T-cells. In the lymph node, B-cells are in the cortex and T-cells are in the paracortex, so you will have enlargement of the lymph node’s paracortex.
A 17 year old boy comes to see you complaining of a sore throat, fever and fatigue. Physical exam reveals posterior cervical lymphadenopathy and splenomegaly. Labs reveal a high white count and atypical lymphocytes. What area of the spleen is causing splenomegaly?
The red pulp of the spleen contains blood. The white pulp contains lymphoid tissue, which contains B cell and T cell areas. The periarterial lymphatic sheath (PALS) in the white pulp is where the T-cells are and will be expanded when patients have an EBV infection, causing splenomegaly.
A 17 year old boy comes to see you complaining of a sore throat, fever and fatigue. Physical exam reveals posterior cervical lymphadenopathy and splenomegaly. Labs show a high white count and atypical lymphocytes. How are you going to test for disease in this patient?
Monospot test: detects IgM heterophile antibodies (binds sheep/hoarse RBCs). The spot will turn positive within 1 week if he has EBV. Since this is a screening test, diagnosis is confirmed by EBV viral capsid antigen presence. If the monospot test is negative, CMV is the cause.
A 17 year old boy comes to see you complaining of a sore throat, fever and fatigue. Physical exam reveals posterior cervical lymphadenopathy and splenomegaly. Labs show a high white count and atypical lymphocytes. What complications is he at risk for?
Splenic rupture (should avoid contact sports for 1 year), rash if exposed to penicillin, EBV remains dormant in B cells (increases risk for lymphoma and recurrent mononucleosis).
What is the definition of an acute leukemia?
>20% blasts in the bone marrow
What symptoms often present in patients with acute leukemia?
The blasts crowd out the normal hematopoietic cells. This causes sudden-onset anemia (hypoxia), thrombocytopenia (bleeding) and neutropenia (infection).
What would you expect to see on CBC of a patient with acute leukemia?
High WBC. Large, immature cells with punched out nucleoli on peripheral blood smear.
A 7 year old boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear is shown below. How do you proceed from here to narrow your diagnosis?
The patient is presenting with symptoms of acute leukemia, confirmed by blast cells on peripheral blood smear. Now you need to determine if the cell is a myeloblast or a lymphoblast. Myeloblasts will stain positive for myeloperoxidase (or seen visually as Auer rods) and indicates acute myelogenous leukemia. The DNA polymerase, tDt, will be positive in the nucleus of lymphoblasts and indicates acute lymphoblastic leukemia.
A 6 year old Down-Syndrome boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows immature blasts. Labs reveal that the blasts are tDt positive. What is your diagnosis?
There is a high association of ALL with Down Syndrome in kids older than 5 years old. Note that AML:acute megakaryoblastic leukemia more commonly presents before the age of 5.
A 7 year old boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and marrow aspirate shows immature blasts that are tDt positive. What markers to you use to further narrow your diagnosis?
B cell acute lymphoblastic leukemia (the most common type of ALL) classically expresses CD10, 19 and 20. T cell acute lymphoblastic lymphoma classically expresses CD2-8 and does not express CD10. Note that T-cell is called lymphoma because cells are not floating around in the blood.
A 7 year old boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows immature blasts that are tDt, CD10, CD19 and CD20 positive. How do you treat this boy?
B-ALL has an excellent response to chemotherapy. However, you must remember that it requires prophylaxis to the scrotum and CSF because the chemotherapy cannot cross the BBB or the blood-testicle barrier.
A 7 year old boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows immature blasts that are tDt, CD10, CD19 and CD20 positive. How do you determine his prognosis?
Cytogenic abnormalities. The good prognosis is more common in kids and is due to t(12;21). The poor prognosis is more common in adults and is due to t(9;22), we call this the Philadelphia + ALL…note that the Philadelphia chromosome is a classic defining feature of CML
A 17 year old boy presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and marrow aspirate shows immature blasts that are tDt and CD2-8 positive. What would you expect to see on physical exam of this patient?
Mediastinal (thymic) mass is a typical presentation in acute lymphoblastic lymphoma.
A 55 year old woman presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear is shown below. What is causing her condition?
Note the Auer rod in the myeloblast on peripheral blood smear, which is precipitated myeloperoxidase in the cytoplasm. This indicates acute myelogenous leukemia, which typically presents in older adults.
A 55 year old woman presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows blasts with numerous Auer rods. What would be responsible for this patient having acute promyelocytic leukemia?
Acute promyelocytic leukemia is caused by t(15;17) which disrupts the retinoic acid receptor. This inhibits differentiation of promyelocytes and they accumulate.
A 55 year old woman presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows blasts with numerous Auer rods. A cytogenic abnormality t(15;17) is found. How do you treat this patient?
Since there is a significant amount of myeloperoxidase in the cytoplasm of the promyelocytes in Acute promyelocytic leukemia, the patient is at risk for DIC if lots of it gets released into the blood. You want to give the patient ATRA, a vitamin A derivative, which binds to the disrupted retinoic acid receptor and activates it, allowing the promyelocytes to mature and become neutrophils.
A 55 year old woman presents with sudden onset dyspnea, bleeding from the gums and recurrent infections in the past month. CBC shows high WBC count and peripheral blood smear shows blasts with numerous Auer rods. Further analysis does not reveal any cytogenic abnormalities. How do you further narrow your diagnosis?
This patient has AML not due to a cytogenic abnormality. You need to look at the lineage of the cells. If the patient has Acute Monocytic Leukemia, there will be proliferation of monoblasts that LACK MPO and characteristically infiltrates the gums. If the patient has acute megakaryoblastic leukemia, there will be proliferation of megakaryoblasts that LACK MPO and is associated with Down Syndrome BEFORE age 5.
A 39 year old woman presents with life-threatening infection and hemorrhage. She has a history of breast cancer that was eradicated with chemotherapy and radiation. Bone marrow biopsy reveals hypercellular bone marrow, abnormal WBC maturation with increased blasts <20%. What caused this patient’s condition?
Prior exposure to alkylating agents or radiotherapy can cause myelodysplastic syndrome due to pre-existing dysplasia. Although the cells are abnormal and the marrow is hypercellular, the cells are not getting out and she has cytopenia. Note that she is at risk for progressing to acute myelogenous leukemia (>20% blasts in marrow).
Definition of a chronic leukemia
Neoplastic proliferation of circulating mature lymphocytes
A 65 year old man presents with generalized fatigue. Labs reveal leukocytosis and peripheral blood smear is shown below. What markers would you test for to further narrow your diagnosis?
Note the increased lymphocytes and smudge cells on blood smear. This patient has a neoplastic proliferation of naive B-cells, resulting in chronic lymphocytic leukemia (CLL). These cells co-express CD20 and aberrant CD5. This is interesting because CD5 is normally a T-cell marker.
A 65 year old man presents with generalized fatigue. Labs reveal leukocytosis and peripheral blood smear shows increased lymphocytes and smudge cells. Further analysis reveals that the cells are CD5 and CD20 positive. What is the next step in progression of this disease?
CLL can progress to the lymph nodes and cause lymphadenopathy. At this point it is called small lymphocytic lymphoma (SLL) because it is in a node and not the blood.
A 65 year old man presents with generalized fatigue. Labs reveal leukocytosis and peripheral blood smear shows increased lymphocytes and smudge cells. Further analysis reveals that the cells are CD5 and CD20 positive. What are complications of this disease?
The most common cause of death in patients with CLL is infection due to hypogammaglobulinemia (naive B-cells don’t produce Ig). They can develop autoimmune hemolytic anemia (naive B-cells that produce Ig, produce bad Ig that reacts against RBCs). Finally, SLL can transform to large B-cell lymphoma, which is more aggressive and presents with rapidly enlarging lymph node masses and splenomegaly.
A 65 year old man presents with generalized fatigue. Physical exam reveals splenomegaly and no lymphadenopathy. Labs reveal leukocytosis and peripheral blood smear is shown below. Bone marrow aspiration resulted in a dry tap. What stain would you do to confirm your diagnosis?
The mature B cells in Hairy Cell Leukemia are positive for tartrate resistant acid phosphatase (TRAP +)
A 65 year old man presents with generalized fatigue. Physical exam reveals splenomegaly and no lymphadenopathy. Labs reveal leukocytosis and peripheral blood smear is shown below. Bone marrow aspiration resulted in a dry tap. What is responsible for his splenomegaly and dry tap?
Expansion of the red pulp causes splenomegaly. Dry tap on bone marrow aspiration is due to fibrosis of the bone marrow in Hairy Cell Leukemia.
A 65 year old man presents with generalized fatigue. Physical exam reveals splenomegaly and no lymphadenopathy. Labs reveal leukocytosis and peripheral blood smear shows mature B cells that are TRAP positive. Bone marrow aspiration resulted in a dry tap. How do you treat this man?
Hairy cell leukemia has an excellent response to 2-CDA, an adenosine deaminase inhibitor. This works because inhibition of adenosine deaminase causes toxic accumulation of adenosine in the neoplastic B cells and causes them to die.
A 65 year old man presents with generalized fatigue and a rash. Physical exam reveals generalized lymphadenopathy and hepatosplenomegaly. Labs reveal leukocytosis, hypercalcemia and lytic bone lesions. He recently went to visit his parents in Japan and his brother in the Caribbean. What is causing his symptoms?
This is the CD4+ neoplastic T-cell proliferation: adult T-cell leukemia lymphoma (ATLL). This is associated with the virus HTLV-1, commonly seen in Japan and the Caribbean.
A 44 year old man presents with multiple rashes, plaques and nodules all over his body. Biopsy reveals aggregates of neoplastic T-cells in the epidermis. After some time the T-cells move to the blood. What would you expect to see on peripheral blood smear?
When T-cells move to the blood from a mycosis fungoides infection, they cause Sezary syndrome. One PB you would see characteristic lymphocytes with cerebriform nuclei (looks like there are lots of folds and lobes).
A 28 year old woman presents with fatigue, weight loss, night sweats and gout. Labs reveal an increased WBC, RBC and platelet count, with WBC predominating. Her peripheral blood smear is shown below. If you rule out infection, what do you think is causing her condition?
Note the increased number of granulocytes, early precursor granulocytes and basophils. This patient has chronic myeloid leukemia. This is a neoplastic accumulation of mature myeloid cells with predominance of granulocytes. Basophils are characteristically increased.
A 28 year old woman presents with fatigue, weight loss, night sweats and gout. Labs reveal an increased WBC, RBC and platelet count, with WBC predominating. Her peripheral blood smear is shown below. What genetic change is responsible for development of her condition? How would you treat her?
Chronic myeloid leukemia arises as a result of t(9;22) that fuses BCR-ABL. This increases tyrosine kinase activity and causes overgrowth of cells. Consequently, you would treat with imatinib, which blocks tyrosine kinase activity.
What conditions are you thinking of when you see this peripheral blood smear?
Iron-deficiency anemia or polycythemia vera, both associated with overproduction of platelets.
A 32 year old woman presents with increased infections, thrombosis and bleeding. Physical exam reveals splenomegaly. Bone marrow biopsy is shown below. What is causing her condition?
Note the pink collagen deposited in the marrow space around the spicule of bone. This patient has Myelofibrosis due to neoplastic proliferation of mature myeloid cells, with megakaryocytes predominating. Marrow fibrosis occurs because of excess PDGF production, which causes extramedullary hematopoiesis and accounts for her splenomegaly. This is associated with JAK2 kinase mutations.
A 32 year old woman presents with increased infections, thrombosis and bleeding. Physical exam reveals splenomegaly. Bone marrow biopsy is shown below. She is diagnosed with myelofibrosis. What would you expect to see on peripheral blood smear.
The bone marrow contains reticulin gates that prevent immature cells to enter the blood. The marrow is fibrosed in patients with myelofibrosis. When extramedullary hematopoiesis occurs in the spleen, you see leukoerythroblastic smear and nucleated red blood cells because the immature cells can enter the blood whenever they please. You would also see tear-drop cells that squeezed out of the fibrosed bone marrow.
What are the normal regions of a lymph node and what cells live in these regions?
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What are the normal zones of the B cell area of the lymph node? How does this relate to lymphomas?
These are the regions where small, well-differentiated B-cell lymphomas arise from: follicular lymphomas, mantle lymphomas and marginal lymphomas.
A 29 year old man presents with painless generalized lymphadenopathy. Lymph node biopsy is shown below. What marker would you expect these cells to be positive for?
Follicular lymphoma small B cells are CD20+.
A 29 year old man presents with painless generalized lymphadenopathy. Lymph node biopsy is shown below. What genetic abnormality is likely contributing to his condition?
Follicular lymphoma is caused by t(14;18). The BCL2 gene on 18 now sits where Ig heavy chain on 14 was originally sitting. Ig heavy chain is a highly active gene in B cells. BCL2 becomes highly active and overexpressed. BCL2 stabilizes the mitochondrial membrane, which prohibits leaking of cytochrome C into the cytoplasm and blocks apoptosis. In the lymph node follicle you need apoptosis to occur because you get somatic hypermutation of the B cells as they differentiate. Poorly developed B cells fail to apoptose due to this mutation and you get a lymphoma.
A 29 year old man presents with painless generalized lymphadenopathy. Lymph node biopsy is shown below. How do you treat this patient?
Follicular lymphoma is treated when patients become symptomatic. They are treated with low-dose chemotherapy or rituximab (antibody against CD20+ cells)
A 29 year old man presents with painless generalized lymphadenopathy. Lymph node biopsy is shown below. He says that he feels like the lymph nodes have been growing over the past few months. What is your diagnosis?
Follicular lymphoma can progress to diffuse large B-cell lymphoma due to additional mutations.
How can you distinguish follicular lymphoma from follicular hyperplasia from an infection?
Follicular lymphoma: 1) Expansion of follicles that go deep and destroy the lymph node architecture 2) Lack of tingible body macrophages in germinal center (shown below) 3) BCL2 expressed in follicles 4) Monoclonality (20:1 kappa:lambda light chain, as apposed to polyclonal proliferations which are 3:1) indicates neoplastic proliferation
Two patients come to see you in clinic. One is a 7 year old African child with a mass around his jaw. The other is a 19 year old man with a mass in his abdomen. What is causing their condition?
These patients have Burkitt lymphoma, a neoplastic proliferation of intermediate-sized B cells (CD20+). t(8;14) causes the c-myc gene on 8 to the spot where Ig was sitting on 14, causing its overexpression. C-myc is an oncogene and promotes cell growth.
Two patients come to see you in clinic. One is a 7 year old African child with a mass around his jaw. The other is a 19 year old man with a mass in his abdomen. What would your expect to see on biopsy of these nodes?
Burkitt lymphoma has c-myc overactivity which cause a very high mitotic rate. This results in a “starry-sky” appearance on histology (sea of neoplastic B cells with clearing out caused by macrophages inducing apoptosis).
What is this cell? What markers does it likely express?
Reed-Sternberg cell (owl-eyed nucleus). Note the large B cell with multilobed nuclei and prominent nucleoli. This would be positive for CD15 and CD30 and negative for CD20.
A 21 year old woman presents with enlarging cervical neck and mediastinal lymph nodes. Lymph node biopsy is shown below. What is your diagnosis? What would you expect to see on higher power?
Note the lymph node divided into nodules by broad bands of fibrosis. She has nodular sclerosis subtype Hodgkin lymphoma. On higher power you would see lacunar cells (Reed-Sternberg cells sitting in cleared out spaces)
A patient presents with bone pain and recent multiple fractures. Labs reveal hypercalcemia. What malignancy is likely causing her condition?
In multiple myeloma, neoplastic plasma cells produce osteoclast activating factor which activates RANK on osteoclasts that causes them to eat away at bone. Note the punched out lesions on X-ray.
A patient presents with bone pain and recent multiple fractures. X-ray reveals multiple punched out lesions in the calvarium. Labs reveal hypercalcemia. What other lab values would you expect to see in this patient?
In multiple myeloma you see increased serum IL-6, hypercalcemia, elevated serum protein (serum protein electrophoresis, or SPEP, will show an M-spike from monoclonal IgG or IgA, but most often IgG) and Rouleaux formation on blood smear (increased serum protein decreases RBC repelling charges)
You see a 70 year old patient in clinic with a high serum protein. When you do the SPEP you see an M-spike. On x-ray there are no lytic lesions. On UA there are no Bence-Jones proteins. Hypercalcemia is absent and there is no AL amyloid deposition. What is your diagnosis?
Monoclonal gammopathy of undetermined significance (MGUS). 1% of these patients will go on to develop multiple myeloma.
What is your diagnosis? What markers can you test for to confirm your suspicion?
This patient has Langerhans cell histiocytosis. The Birbeck (tennis racket ) granules seen on EM are characteristic of this disease. Cells will be positive for CD1a and S100 on immunohistochemistry.
